Bone regeneration

ABSTRACT

A method for reducing bone resorption at tooth extraction sites by topically applying a prostaglandin inhibitor, such as a non-steroidal anti-inflammatory drug (NSAID) to the affected area. The preferred NSAID is ketoprofen. The composition may also include a penetration enhancer such as vitamin E.

This is a continuation of application Ser. No. 08/574,054, filed Dec.18, 1995, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to methods and compositions for encouraging boneregeneration, especially after tooth loss, using non-steroidalanti-inflammatory drugs (NSAIDs).

2. Description of Related Art

Removing a tooth in dentistry can have consequences that extend farbeyond the loss of the tooth. Resorption of the residual alveolar ridgethat formerly supported the tooth is a chronic localized process thatoccurs following tooth extraction. This bone loss can affect nearby,healthy teeth and can increase the difficulty of fitting dentures andsupporting other replacement dental work. Although the rate of bone lossis most rapid shortly after tooth extraction, resorption may continuelong after the extraction.

Removing a tooth for the purpose of fitting full or partial dentures isa procedure that can often be planned in advance. Therapy can begin evenbefore removal of the tooth or teeth. Extraction mandated by trauma orother emergency conditions, however, often cannot be planned far inadvance, so pre-extraction therapy is not always possible.

Resorption is an especially difficult problem for fitting dentures.Stability, retention, function and the aesthetics of removable denturesare directly affected by alveolar ridge size and shape. Thus, resorptionis an important factor in determining the longevity and clinical outcomeof a removable denture.

Bone resorption is also a difficult problem around dental implants,particularly during the initial loading period.

Often, two different types of dentures are used with a patient. An"immediate" denture is a removable denture inserted on the day of toothextraction. Its purpose is to restore function and alleviate theembarrassment that can occur when the patient is forced to endure anextended period of time without teeth. "Conventional" dentures arefitted later, after initial healing, and are intended to belonger-lasting. Bone loss can have a deleterious effect on the fit andefficacy of both types of dentures. Immediate dentures may need to berefitted by the dentist as soon as a few months after the extraction,and conventional, permanent dentures may need frequent monitoring andalteration or replacement.

Although many dentists do nothing at all to forestall bone loss, thosethat do treat bone loss after extraction do so by placing a material inthe post-extraction socket that at least discourages resorption. Thesematerials include bone from cadavers, hydroxyapatite, and speciallyprocessed glass particles.

Bone is difficult to work with and, if not properly treated, can carrydisease vectors from the donor. Hydroxyapatite is difficult to work withand tends to migrate away from the site. Bioactive glass is anintriguing new product on the market and, although it does not sufferfrom the problems of the other materials, it has not yet gained wideacceptance in the dental market.

Implanted materials have one additional drawback. At best, the materialsact as a matrix for bone growth. They do nothing to reduce or eliminatethe forces that cause resorption in the first place. Thus there is stilla need in the art for a material that, either alone or in combinationwith an implanted material, acts to reduce the forces that encouragebone resorption after tooth extraction. A special need remains in theart for a bone-loss therapy that can be administered during or aftertooth loss, in those instances when pre-extraction therapy isunavailable.

Various studies have been carried out on bone formation usingnon-steroidal anti-inflammatory drugs as agents affecting bone growthand bone structure. One article, Yazdi, M. et al., "Effects ofnonsteroidal anti-inflamatory drugs on Demineralized Bone-induced BoneFormation," J. Periodont Res 1992; 27:28-33, reported the effects ofacetylsalicylic acid, acetarninophen, ibuprofen, indomethacin, prioxicamand flurbiprofen on bone growth over powdered demineralized boneimplanted into para-sternal sites on rats. The various additives (aswell as the control) were injected into the rats in a single dailysubcutaneous injection beginning either three days prior to implantationor three days after implantation. The researchers reported that bothinhibitory and stimulatory effects on bone formation were found in ratstreated before implantation. Despite some encouraging pictures in thearticle, the researchers concluded that pretreating with flurbiprofen"did not appear to significantly affect bone formation," id. at 31,while pretreatment with ibuprofen appeared to enhance bone formation.Id. at 31-32. Treating with NSAIDS after implantation, however, did notappear to affect the rats, "Wile no significant differences betweenexperimental and control groups were observed, there was goodosteoinduction in groups treated with indomethacin . . . piroxicam . . .or flurbiprofen . . . " Id. at 32.

Another research group studied the effects of systemic flurbiprofen ondental implants, Jeffcoat, M. et al., "The Effect of SystemicFlurbiprofen on Bone Supporting Dental Implants," JADA, Vol. 126, March1995, 305-11. The group noted that flurbiprofen, along with others, hadshown the ability to retard alveolar bone loss due to periodontitis butthat the effect of NSAIDS on preventing bone loss in implant situationshad not been established. The researchers studied the effect of a courseof systemic administration of flurbiprofen on titanium implants using 50and 100 mg doses of flurbiprofen. The high dose flurbiprofen dosagereduced bone loss, but showed no increase in bone levels, except for abrief increase in bone mass after three months that subsequentlydisappeared. The researchers concluded, "At first glance, the hypothesisunderlying the effect(s) of NSAIDs on bone may appear deceptivelystraightforward. However, the basic pathophysiology underlying theseagents could be used to support either positive or negative effects onbone." Id. at 310.

SUMMARY OF THE INVENTION

The principal object of the present invention therefore is to provide anagent for reducing the resorption of bone after tooth extraction.

Another object of the invention is to provide an agent for reducing theresorption of bone after tooth extraction that may be used inconjunction with implants or that may be used in conjunction withimmediate dentures. Still another object of the invention is to providea topically administered product for reducing bone loss that may beapplied by the patient, without strict measurement or oversight by thedentist. Another object of the invention is to provide a therapy forpost-extraction bone loss that may be administered after extractiontakes place.

Additional objects and advantages of the invention will be set forth inpart in the description that follows, and in part will be obvious fromthis description, or may be learned by practice of the invention. Theobjects and advantages of the invention may be realized and attained bymeans of the instrumentalities and combinations particularly pointed outin the appended claims.

To achieve the foregoing objects and in accordance with the purpose ofthe invention, as embodied and broadly described herein, the inventionprovides a combination of an anti-inflammatory agent and a penetrationenhancer for application to the site of an extracted tooth. Theseingredients combat bone loss, and they alleviate pain.

To further achieve the foregoing objects and in accordance with thepurpose of the invention, the invention further provides a method forreducing or preventing bone loss after tooth extraction comprising thestep of topically applying an anti-inflammatory drug to the site of anextracted tooth. This step of topical application may be carried out byapplying a creme, gel, lotion or other delivery vehicle containing theactive ingredients to the environs of an extracted tooth or implantdirectly or by applying the delivery vehicle to a denture or otherdental work covering the site, or by impregnating an implant materialwith the active ingredients.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to the presently preferredembodiments of the invention.

One of the first responses of the human body to tooth extraction isinflammation of the site. While inflammation is part of the wound repairmechanism, several mediators released at the site of cell injury canstimulate bone resorption. One of these recognized mediators isprostaglandin E₂ (PGE₂). It has been shown that the prostaglandininhibitor indomethacin inhibits bone resorption, presumably byprostaglandin inhibition. Nishimura, I. et al., "A LocalPathophysiologic Mechanism of the Resorption of Residual Ridges:Prostaglandin as a Mediator of Bone Resorption," The Journal ofProsthetic Dentistry, vol. 60, No. 3, pp. 381-388 (September 1988).(Although this article mentions both indomethacin and flurbiprofen, onlyindomethacin was tested.)

Bone resorption after extraction differs from other conditions becausethere is an acute injury followed by a lengthy period of wound repair.After tooth extraction, a sequence of physiologic events occursinvolving clot formation, connective tissue repairs, osteoid formationand bone remodeling. Thus post extraction bone loss occurs in anenvironment of bone repair, whereas alveolar bone loss due toperiodontal disease is the result of a chronic, bacterially-mediateddestructive process.

To combat bone resorption, the invention contemplates topicaladministration of a non-steroidal anti-inflammatory drug (NSAID) to thearea affected by extraction of the tooth or by an implant. This topicaladministration may be carried out in a number of ways. The NSAID may beapplied as a topical cream or ointment to the surface of the affectedarea. It may be applied to the surface of the dental prosthesis placedover the site of the extraction, either as a separate ointment or aspart of a denture adhesive cream or powder. Preferably, the NSAID isapplied fairly frequently during the early phases of recovery from toothextraction, although less frequent applications may be appropriatethereafter. As will be understood by those skilled in the art, sustainedrelease or other technologies may be employed to affect the releaseprofile of the NSAID to the affected site.

Another delivery system for the NSAID is incorporation into an implantplaced into the affected site. Over time, the NSAID will migrate out ofthe implant and into the surrounding tissue. Although this method isprobably not the most effective method for delivering large amounts ofNSAID into the tissue in a short time, the method is an effective longterm treatment.

The preferred non-steroidal anti-inflammatory drug of the invention isketoprofen, although other non-steroidal anti-inflammatory drugs such asibuprofen or flurbiprofen may be substituted for ketoprofen. Indeed, anyprostaglandin inhibitor may be substituted for ketoprofen.

The NSAID may be delivered in any vehicle that is both capable ofdelivering the NSAID and not overly injurious to the oral environment.The delivery system may be as simple as an aqueous solution orsuspension of the NSAID, or the system may be an ointment or cream madefrom ingredients well known in the art.

Of course, the NSAID) will be more effective if it penetrates more fullyinto the target tissues. Accordingly, one embodiment of the inventioncomprises the combination of an NSAID and a penetration enhancer tocarry the NSAID to the target site to inhibit bone resorption associatedwith an extracted tooth.

Preferred penetration enhancers include known penetration enhancers.Especially preferred are Vitamin E and its analogs, which act totransport the NSAID to the active site without causing systemic effects.

The invention may be made by mixing a therapeutic amount of the NSAID ina conventional cream, gel or other topical medium. Preferably, the NSAIDcomprises up to about 5% by weight of the cream or gel, and morepreferably up to about 3% by weight. If desired, a penetration enhancermay also be added in appropriate amounts. The preferred penetrationenhancer is Vitamin E, and the preferred amount of Vitamin E is up toabout 0.3% of the cream or gel by weight. Higher levels of Vitamin E maybe used, but higher levels do not appear to improve the penetration ofthe NSAID. Of course, different penetration enhancers may have differentlevels of efficacy, and more or less of another penetration enhancer maybe required.

The preferred embodiments of the invention will be made more clear byreference to the following Examples.

EXAMPLES

Application of ketoprofen gel into maxillary dentures was studied involunteer edentulous subjects. One gram of either placebo or 3%ketoprofen gel was applied inside the denture each morning and eveningover a twenty-four (24) week test period. In one test cell straight 3%ketoprofen gel was used, in a second cell a placebo was used, and in athird cell, ketoprofen gel was used for a period of four weeks and thenplacebo was used for 20 weeks.

The formulation for the ketoprofen gel contained 3% ketoprofen in apluronic/water gel base. Polycarbophil was added as a mucosal adhesive,vitamin E was added as a penetration enhancer, and the gel was adjustedto a pH within the range of 4.5 to about 7.0.

Intra-oral Radiographs were taken at day 84 and day 168 of treatment,and the change in bone height was measured in pixels of a digitizedimage of the radiograph. The number of patients, the mean, the standarddeviation, the median and the range were recorded and were set out inTable 1. The same figures were also calculated on a percentage basis andare also set forth in Table 1.

The results obtained in Table 1 show that there is a significantreduction in bone resorption, even for the partial treatment.

                                      TABLE 1    __________________________________________________________________________    Summary Statistics and Analysis of    Ketoprofen Gel for Oral Use          3%      3%          ketoprofen                  ketoprofen      P value for    Properties          gel for 6                  gel for 1       overall                                        P value for                                               P value for                                                      P value for    Measured          months  month   Placebo treatment                                        Col.1 v. Col.2                                               Col.1 v. Col.3                                                      Col.2 v.    __________________________________________________________________________                                                      Col.3    Change in          N = 10  N = 12  N = 9   ≦0.05                                        0.396  0.046  0.191    Bone Height          Mean = 10.30                  Mean = 13.28                          Mean = 18.05    (measured in          Std.    Std.    Std.    pixels of          Dev. = 6.563                  Dev. = 7.821                          Dev. = 9.757    intraoral          Med. = 8.66                  Med. = 13.36                          Med. = 13.34    radiograph)          Range = 0.00-                  Range = 3.16-                          Range = 7.62-    Day 84          24.19   26.08   34.01    Change in          N = 10  N = 11  N = 9   ≦0.05                                        0.440  0.059  0.220    Bone Height          Mean = 16.76                  Mean = 20.14                          Mean = 25.72    (measured in          Std.    Std.    Std.    pixels of          Dev. = 6.152                  Dev. = 11.844                          Dev. = 10.570    intraoral          Med. = 16.34                  Med. = 22.00                          Med. = 26.08    radiograph)          Range = 6.08-                  Range = 4.12-                          Range = 10.05-    Day 168          27.66   46.00   41.01    Change in          N = 10  N = 12  N = 9   ≦0.05                                        0.804  0.040  0.056    Bone Area          Mean = 21.94                  Mean = 23.75                          Mean = 38.67    (on a Std.    Std.    Std.    percentage          Dev. = 10.806                  Dev. = 17.400                          Dev. = 21.386    basis)          Med. = 18.67                  Med. = 18.90                          Med. = 29.22    Day 84          Range = 8.11-                  Range = 1.890-                          Range = 16.00-          45.78   64.56   78.56    Change in          N = 10  N = 11  N = 9   ≦0.05                                        0.826  0.092  0.055    Bone Area          Mean = 33.68                  Mean = 31.71                          Mean = 49.99    (on a Std.    Std.    Std.    percentage          Dev. = 16.02                  Dev. = 24.129                          Dev. = 19.368    basis)          Med. = 29.45                  Med. = 30.89                          Med. = 49.78    Day 168          Range = 15.45-                  Range = 5.110-                          Range = 22.00-          67.45   86.00   89.89    __________________________________________________________________________

As shown in Table 1, topical treatment with ketoprofen providessignificant benefits in treating bone resorption on extraction siteseven if the treatment is only relatively short term. A longer termcourse of therapy may be even more beneficial and is the preferred formof treatment. None of the prior art would have suggested such a dramaticeffect of topical application of an NSAID such as ketoprofen on thealveolar bone level of humans subjected to tooth extraction trauma.

The purpose of the above description is to illustrate some embodimentsof the present invention without implying a limitation. It will beapparent to those skilled in the art that various modifications andvariations may be made in the apparatus or procedure of the inventionwithout departing from the scope or spirit of the invention.

What is claimed is:
 1. A method for reducing bone resorption in toothextraction or implant sites comprising the step of topically applying atherapeutic amount of a composition comprising ketoprofen and apenetration enhancer to the site of the tooth extraction or implant. 2.The method of claim 1, wherein said penetration enhancer is selectedfrom the group consisting of vitamin E and its analogs.
 3. The method ofclaim 1, wherein said composition is applied to the surface of a dentureor other prosthetic device that is to be exposed to the site of a toothextraction or implant.
 4. The method of claim 3, wherein saidcomposition comprises a denture adhesive or powder.
 5. The method ofclaim 1, wherein said therapeutic amount is applied after extraction ofthe tooth.
 6. The method of claim 1, wherein said therapeutic amount isapplied periodically to the site of the tooth extraction or implant.